The pathophysiology and genetics of congenital lipoid adrenal hyperplasia
The pathophysiology and genetics of congenital lipoid adrenal hyperplasia
复制标题
DOI：
10.1056/nejm199612193352503
复制
发表时间：
1996-12-19
影响因子：
158.5
通讯作者：
Miller, WL
中科院分区：
文献类型：
--
作者：
Bose, HS;Sugawara, T;Miller, WL
先天性类脂质肾上腺增生导致肾上腺和性腺类固醇生物合成严重受损，在子宫内和出生后均表现出来。我们最近在四名患有这种综合征的患者中发现了类固醇生成急性调节蛋白基因的突变，但尚不清楚是否所有患者都有这样的突变，也不清楚为什么这些患者中存在大量的临床变异。方法对来自10个国家的15例先天性类脂质肾上腺皮质增生症患者的类固醇生成急性调节蛋白基因进行直接测序。对识别出的突变进行确认并在表达载体中重建，转染到培养细胞中，并检测类固醇生成急性调节蛋白的存在和活性。结果在14名患者中发现类固醇生成急性调节蛋白基因存在15种不同的突变;突变Gln 258 Stop在日本和韩国患者80%的受影响等位基因中发现，在巴勒斯坦患者中，78%的受影响等位基因中发现了Arg 182 Leu突变。我们开发了针对这些和其他八种突变的诊断测试。15个突变中有13个位于外显子5、6或7，并且在功能测定中均使类固醇生成急性调节蛋白失活。一些突变体的氨基酸置换能够正常的线粒体加工，表明类固醇生成急性调节蛋白的活动是不相关的，其易位到线粒体。缺乏该蛋白质的类固醇生成细胞保持低水平的类固醇生成。这解释了在青春期后，在受影响的细胞积累大量胆固醇酯之前，卵巢分泌一些类固醇激素。结论先天性类脂质肾上腺皮质增生表型是两个独立事件的结果，一个是依赖于类固醇生成急性调节蛋白的类固醇生成的初始遗传丢失，一个是由于积累的胆固醇酯引起的细胞损伤而导致的不依赖于该蛋白的类固醇生成的随后丢失。
Background Congenital lipoid adrenal hyperplasia results in severe impairment of steroid biosynthesis in the adrenal glands and gonads that is manifested both in utero and postnatally. We recently found mutations in the gene for the steroidogenic acute regulatory protein in four patients with this syndrome, but it was not clear whether all patients have such mutations or why there is substantial clinical variation in these patients. Methods We directly sequenced the gene for steroidogenic acute regulatory protein in 15 patients with congenital lipoid adrenal hyperplasia from 10 countries. Identified mutations were confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein.Results Fifteen different mutations in the gene for steroidogenic acute regulatory protein were found in 14 patients; the mutation Gln258Stop was found in 80 percent of affected alleles from Japanese and Korean patients, and the mutation Arg182Leu was found in 78 percent of affected alleles from Palestinian patients. We developed diagnostic tests for these and eight other mutations. Thirteen of the 15 mutations were in exons 5, 6, or 7, and all rendered the steroidogenic acute regulatory protein inactive in functional assays. Some mutants with amino acid replacements were capable of normal mitochondrial processing, indicating that the activity of steroidogenic acute regulatory protein is not associated with its translocation into mitochondria. Steroidogenic cells lacking the protein retained low levels of steroidogenesis. This explains the secretion of some steroid hormones by the ovaries after puberty before affected cells accumulate large amounts of cholesterol esters. Conclusions The congenital lipoid adrenal hyperplasia phenotype is the result of two separate events, an initial genetic toss of steroidogenesis that is dependent on steroidogenic acute regulatory protein and a subsequent loss of steroidogenesis that is independent of the protein due to cellular damage from accumulated cholesterol esters.